Essential Dynamics Ensemble Docking for Structure-Based GPCR Drug Discovery
The lack of biologically relevant protein structures can hinder rational design of small molecules to target G protein-coupled receptors (GPCRs). While ensemble docking using multiple models of the protein target is a promising technique for structure-based drug discovery, model clustering and selec...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-06-01
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| Series: | Frontiers in Molecular Biosciences |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fmolb.2022.879212/full |
| _version_ | 1811237108806844416 |
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| author | Kyle McKay Nicholas B. Hamilton Jacob M. Remington Severin T. Schneebeli Jianing Li |
| author_facet | Kyle McKay Nicholas B. Hamilton Jacob M. Remington Severin T. Schneebeli Jianing Li |
| author_sort | Kyle McKay |
| collection | DOAJ |
| description | The lack of biologically relevant protein structures can hinder rational design of small molecules to target G protein-coupled receptors (GPCRs). While ensemble docking using multiple models of the protein target is a promising technique for structure-based drug discovery, model clustering and selection still need further investigations to achieve both high accuracy and efficiency. In this work, we have developed an original ensemble docking approach, which identifies the most relevant conformations based on the essential dynamics of the protein pocket. This approach is applied to the study of small-molecule antagonists for the PAC1 receptor, a class B GPCR and a regulator of stress. As few as four representative PAC1 models are selected from simulations of a homology model and then used to screen three million compounds from the ZINC database and 23 experimentally validated compounds for PAC1 targeting. Our essential dynamics ensemble docking (EDED) approach can effectively reduce the number of false negatives in virtual screening and improve the accuracy to seek potent compounds. Given the cost and difficulties to determine membrane protein structures for all the relevant states, our methodology can be useful for future discovery of small molecules to target more other GPCRs, either with or without experimental structures. |
| first_indexed | 2024-04-12T12:20:25Z |
| format | Article |
| id | doaj.art-cf0dcf8afb874bad88fbd8103b278822 |
| institution | Directory Open Access Journal |
| issn | 2296-889X |
| language | English |
| last_indexed | 2024-04-12T12:20:25Z |
| publishDate | 2022-06-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Molecular Biosciences |
| spelling | doaj.art-cf0dcf8afb874bad88fbd8103b2788222022-12-22T03:33:19ZengFrontiers Media S.A.Frontiers in Molecular Biosciences2296-889X2022-06-01910.3389/fmolb.2022.879212879212Essential Dynamics Ensemble Docking for Structure-Based GPCR Drug DiscoveryKyle McKayNicholas B. HamiltonJacob M. RemingtonSeverin T. SchneebeliJianing LiThe lack of biologically relevant protein structures can hinder rational design of small molecules to target G protein-coupled receptors (GPCRs). While ensemble docking using multiple models of the protein target is a promising technique for structure-based drug discovery, model clustering and selection still need further investigations to achieve both high accuracy and efficiency. In this work, we have developed an original ensemble docking approach, which identifies the most relevant conformations based on the essential dynamics of the protein pocket. This approach is applied to the study of small-molecule antagonists for the PAC1 receptor, a class B GPCR and a regulator of stress. As few as four representative PAC1 models are selected from simulations of a homology model and then used to screen three million compounds from the ZINC database and 23 experimentally validated compounds for PAC1 targeting. Our essential dynamics ensemble docking (EDED) approach can effectively reduce the number of false negatives in virtual screening and improve the accuracy to seek potent compounds. Given the cost and difficulties to determine membrane protein structures for all the relevant states, our methodology can be useful for future discovery of small molecules to target more other GPCRs, either with or without experimental structures.https://www.frontiersin.org/articles/10.3389/fmolb.2022.879212/fullcomputer aided drug designPAC1 receptorantagonistvirtual screeningmolecular dynamicsprincipal component analysis |
| spellingShingle | Kyle McKay Nicholas B. Hamilton Jacob M. Remington Severin T. Schneebeli Jianing Li Essential Dynamics Ensemble Docking for Structure-Based GPCR Drug Discovery Frontiers in Molecular Biosciences computer aided drug design PAC1 receptor antagonist virtual screening molecular dynamics principal component analysis |
| title | Essential Dynamics Ensemble Docking for Structure-Based GPCR Drug Discovery |
| title_full | Essential Dynamics Ensemble Docking for Structure-Based GPCR Drug Discovery |
| title_fullStr | Essential Dynamics Ensemble Docking for Structure-Based GPCR Drug Discovery |
| title_full_unstemmed | Essential Dynamics Ensemble Docking for Structure-Based GPCR Drug Discovery |
| title_short | Essential Dynamics Ensemble Docking for Structure-Based GPCR Drug Discovery |
| title_sort | essential dynamics ensemble docking for structure based gpcr drug discovery |
| topic | computer aided drug design PAC1 receptor antagonist virtual screening molecular dynamics principal component analysis |
| url | https://www.frontiersin.org/articles/10.3389/fmolb.2022.879212/full |
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